EP3122721A1 - Ror-gamma modulators and uses thereof - Google Patents
Ror-gamma modulators and uses thereofInfo
- Publication number
- EP3122721A1 EP3122721A1 EP15769739.2A EP15769739A EP3122721A1 EP 3122721 A1 EP3122721 A1 EP 3122721A1 EP 15769739 A EP15769739 A EP 15769739A EP 3122721 A1 EP3122721 A1 EP 3122721A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- phenyl
- acetamide
- ethylsulfonyl
- hexafluoro
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
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- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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Definitions
- the present invention relates to the compounds of formula I (as described herein), processes for their preparation, pharmaceutical compositions containing them and their use as retinoid related orphan receptor gamma (RORy) modulators, and methods of using said compounds in the treatment of diseases mediated by RORy.
- RORy retinoid related orphan receptor gamma
- Nuclear receptors are ligand-regulated transcription factors that play diverse role in the expression of target genes associated with physiological processes such as cell differentiation, development, metabolism and immunity. All members of the nuclear receptors super family are multi domain proteins. Majority of the nuclear receptors contain the four functional domains, namely N-terminal "A/B domain", DNA-binding domain or "C domain”, highly variable hinge or "D domain”, and C-terminal ligand-binding domain (LBD) or "E domain".
- Several NRs contain a highly variable C-terminal F domain.
- RORs Retinoid-related orphan receptors
- NRs nuclear receptors
- the ROR subfamily consists of three isoforms, namely RORalpha (RORa), RORbeta (RORP) and RORgamma (RORy), which are also referred to as NR1F1, NR1F2 and NR1F3 respectively.
- RORa, RORP and RORy function as ligand dependent transcription factors and recent research studies suggest that RORs may be potential therapeutic targets for treatment of various diseases.
- Each of the RORs is encoded by a distinct gene RORA, RORB and RORC and each ROR gene generates several isoforms, differing only in their N-terminal "A/B domain".
- RORa al-4
- RORy two isoforms have been identified, and RORP gene is expressed in only one isoform in humans, whereas for RORy, two isoforms have been identified namely RORyl and RORy2.
- the isoform "RORy2" is commonly known as RORyt.
- RORy2 (RORyt) is exclusively detected in a few distinct cell types of the immune system, for instance, in thymus ⁇ Journal of Experimental Pharmacology, 2012, 4, 141-148; Nuclear Receptor Signaling, 2009, 7, 1-32) while RORyl is expressed in many tissues, including thymus, lung, liver, kidney, skeletal muscle, adipose tissue and skin. RORyt has been identified as a key regulator of Thl7 cell differentiation ⁇ Nuclear Receptor Signalling, 2009, 7, 1-32; International Immunopharmacology, 2011, 11, 536-542).
- Thl7 (T helper 17) cells constitute a distinct subset of CD4 + helper T cells that are mainly characterized by abundant interleukin (IL)-17 production. They are developmental ⁇ distinct from Thl and Th2 cells, which are the other two subsets of T helper cells.
- the Thl7 cells are known to be involved in the host defence against bacteria and fungi and also in the pathogenesis of autoimmune diseases. Thus, it is reported that Thl7 cells play a critical role in many inflammatory and autoimmune diseases (Immunological Reviews, 2008, 223, 87- 113).
- Thl7 cells have a key role in cancer and a variety of autoimmune diseases such as collagen-induced arthritis (CIA), inflammatory bowel disease (IBD) and graft versus host disease (GVHD) (Blood and Marrow Transplantation, 2012, 18, S56-61).
- CIA collagen-induced arthritis
- IBD inflammatory bowel disease
- GVHD graft versus host disease
- Asthma is a chronic inflammatory disorder of airways, in the pathogenesis of which Thl7 cells/IL-17 play a key role.
- both RORyt and IL-17A expression levels have been shown to be increased in sputum, lung, bronchoalveolar lavage (BAL) fluids and peripheral blood and these levels directly correlate with disease severity.
- BAL bronchoalveolar lavage
- IL-17F another cytokine of the IL-17 family, IL-17F, may have a crucial role in allergic airway inflammation and hence, have key implications in airway diseases, such as asthma (Respiratory Research, 2010, 11 :78, 1-11).
- Thl7 cells are one of the important drivers of the inflammatory process in tissue - specific autoimmunity (Journal of Experimental Medicine, 2008, 205, 1517-1522; Cellular and Molecular Immunology, 2010, 7, 182-189). Also, during the disease process Thl7 cells are activated and are responsible for recruiting other inflammatory cells types, particularly neutrophils, to mediate pathology in the target tissues.
- RORyt has been shown to play a critical role in the differentiation of Thl7 cells and IL-17 expression. RORyt deficiency results in diminished Thl7 activity and severely reduced expression of IL-17. Several studies suggest that RORyt plays a vital role in various diseases or disorders (Journal of Experimental Pharmacology, 2012, 4, 141-148).
- the present invention relates to a compound of formula I (as described herein), or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, S-oxide or an N-oxide thereof.
- compositions comprising a compound of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; and at least one pharmaceutically acceptable carrier or excipient.
- RORy retinoid related orphan receptor gamma
- a compound of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof for use in the treatment of a disease or a disorder mediated by RORy.
- a method for the treatment of a disease or disorder mediated by RORy comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof.
- the present invention relates to use of a compound of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; in combination with at least one further therapeutically active agent; for the treatment of a disease or disorder mediated by RORy
- the present invention relates to a compound of formula I,
- R a is (d-Cg)-aikyl, (C 3 -C 12 )-cycloalkyl, (C 6 -C 10 )-aryl or heterocyclyl;
- R b and R c at each occurrence are independently selected from the group consisting of hydrogen, (Ci-Cg)-alkyl, (C3-Ci2)-cycloalkyl, (Ce-Cio)-aryl and heterocyclyl; or
- R b and R c can combine to form a saturated or unsaturated 5- or 6-membered ring, optionally containing 1 or 2 additional heteroatoms selected from the group consisting of N, S and O; wherein the ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, oxo, (C 1 -Cg)-alkoxy and halo(C 1 -Cg)-alkyl;
- R d is (C 1 -Cg)-alkyl-0-(C 1 -Cg)-alkyl or halo(C 1 -C 8 )-alkyl;
- R e is hydrogen, (C 1 -Cg)-alkyl, (d-Cg)-alkoxy, halo(CrCg)-alkyl, (C 2 -Cg)-alkenyl or NR al R a2 ;
- X is O, NH, S(0) 2 or S;
- n 0, 1 or 2;
- n 0 or 1 ;
- R at each occurrence is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (Ci-Cg)-alkyl, (Ci-Cg)-alkoxy, (C3-Ci2)-cycloalkyl, halo(Ci-Cg)- alkyl, halo(Ci-C 8 )-alkoxy, NR ⁇ R 32 , COR 33 , COOR a3 and CONR ⁇ R 32 ; or
- R a R when present on adjacent carbon atoms of the phenyl can combine to form a saturated 5- or 6-membered ring containing S or S(3 ⁇ 4; which ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, cyano, oxo, (Ci-Cg)-alkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (Ci-Cg)-alkoxy and halo(C Cg)-alkyl;
- R J and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (Ci-Cg)-alkyl, (C2-Cg)-alkenyl, (Ci-Cg)-alkoxy and halo(Ci-Cg)aikyl;
- a is 1 or 2;
- b is 1 or 2;
- L is -CO- or -SO2-
- R 5 is hydrogen, (Ci-Cg)-alkyl, halo(Ci-Cg)alkyl or (C 3 -Ci2)-cycloalkyl;
- R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (Ci-Cg)-alkyl, (C2-Cg)-alkenyl, (Ci-Cg)-alkoxy, halo(Ci-Cg)aikyl, (C 3 - C 12 )-cycloalkyl, (C 6 -C 10 )-aryl, CONR ⁇ R 32 , COR 33 and COOR a3 ; or
- R 6 and R 7 can combine to form saturated or unsaturated 3-6 membered cyclic ring optionally containing 1 or 2 heteroatoms selected from the group consisting of O, N and S; wherein the ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of oxo, hydroxy, cyano, halogen, (Ci -
- R is hydrogen, halogen, hydroxy, cyano, (Ci-Cg)-alkyl, (C2-Cg)-alkenyl, (Ci-Cg)- alkoxy, halo(C Cg)alkyl, CONR al R , COR aJ or COOR aJ ;
- T is CR' or N
- R is hydrogen, cyano, halogen, (Ci-Cg)-alkyl, (Ci-Cg)-alkoxy, (C 3 -Ci2)-cycloalkyl, halo(Ci-Cg)-alkyl or halo(Ci-Cg)-alkoxy; c is 0, 1, 2 or 3;
- d is 1 or 2;
- R 9 is (CR f R j ) f R b (CR f R j ) f OR k , (CR f R j ) f N(R k ) 2 , (CR f R j ) f CN, (CR f R j )rhalogen, W-(C 3 -C 12 )- cycloalkyl, W-(Cs-Cio)-cycloalkenyl, W 1 -(C6-Cio)-aryl, W 1 -heterocyclyl or W 1 -heteroaryl;
- R 10 at each occurrence is independently selected from the group consisting of (CR f R ⁇ ) f OR k , oxo, W-(C 3 -C 12 )-cycloaikyl, (C 6 -C 10 )-aryl, W 1 -(C 6 -C 10 )-aryl and W 1 -heteroaryl;
- R k is hydrogen, (Ci-Cg)-alkyl, (C3-Ci2)-cycloalkyl, (Cs-Cio)-cycloalkenyl, -(Ci-Cg)-alkylene- (C 3 -C 12 )-cycloalkyl, -(C 1 -Cg)-alkylene-(C 5 -C 10 )-cycloalkenyl, (C 6 -C 10 )-aryl, -(C Cg)- alkylene-(C6-C 1 o)-aryl, heteroaryl, heterocyclyl, or -(Cj-Cg)- alkylene-heterocyclyl ;
- R x and R y at each occurrence are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, oxo, (Ci-Cg)-alkyl, (Ci-Cg)-alkoxy, (C3-Ci2)-cycloalkyl, halo(C Cg)-alkyl, halo(C Cg)-alkoxy, NR al R a2 , COR a3 , COOR 33 and CONR ⁇ R 32 ;
- W is a bond, -0-, CO, NH, (CR f R g ) f , (CR f R g ) f -C ⁇ C- or (C 5 -C 10 )-cycloalkenyl;
- W 1 is (CR f R j ) f , (CR f R g ) f -C ⁇ C- or (C 5 -C 10 )-cycloalkenyl;
- R j is (CrCg)alkyl, (d-Cg)alkoxy, halo(C 1 -Cg)alkyl, COOR a3 or heterocyclyl;
- R f and R g are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, (C 1 -Cg)alkyl and halo(C 1 -Cg)alkyl;
- e 1 or 2;
- f 1, 2, 3 or 4;
- o 0, 1, 2 or 3;
- R 11 is hydrogen, (Ci-Cg)-alkyl, (C3-Ci2)-cycloalkyl, (C5-Cio)-cycloalkenyl, (Ce-Cio)-aryl, (CR f R g ) f -(C 6 -C 10 )-aryl, (CR f R g ) r heterocyclyl, COOR a3 or COR 33 ;
- X 1 is CR 12 R 13 , O, S or S(0) 2 ;
- X 3 is O or S;
- X 4 is CR 17 or N
- X 5 is CR 18 R 19 or S
- t 0, 1 or 2;
- s 1 or 2;
- R , R 1J , R , R 1J , R , R and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (Ci-Cg)-alkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (Ci- Cg)-alkoxy, (C3-Ci2)-cycloalkyl, (Cs-Cio)-cycloalkenyl, halo(Ci-Cg)-alkyl, (Ce-Cio)-aryl, heteroaryl, heterocyclyl, NR al R a2 , COR 33 , COOR a3 , CONR al R a2 , S(0) q (C ! -Cg)-alkyl and SCO NR ⁇ R* 2 ;
- R 16 is O, (C 3 -Ci2)-cycloalkyl, (Cs-Cio)-cycloalkenyl or heterocyclyl;
- R al , R 32 and R a3 at each occurrence are independently selected from the group consisting of hydrogen, (Ci-Cg)-alkyl and (C 3 -Ci2)-cycloalkyl;
- q 0, 1 or 2;
- each of the (Ci-Cg)-alkyl, (Ci-Cg)-alkylene, (C2-Cg)-alkenyl and (Ci-Cg)-alkoxy can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (Ci-Cg)-alkynyl, (Ci-Cg)-alkoxy, (C 3 -C 1 2)- cycloalkyl, (C 6 -Cio)-aryl, heterocyclyl, heteroaryl, halo(Ci-Cg)alkoxy, C(0)R h , OC(0)R h , COOR h , C(0)NR h R i , 0-R ⁇ OC(0)NR h R i , NR h R ⁇ NR h C(0)R i , NR h C(0)NR h R i , S(0) q (C Cg)
- each of the (C 3 -Ci2)-cycloalkyl, (C5-Cio)-cycloalkenyl and (Ce-Cio)-aryl can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (C 1 -Cg)-alkyl, (CrCg)-alkoxy, ( C ⁇ -cycloalkyl, (Ce-Cjo)- aryl, heterocyclyl, heteroaryl, halo(Ci-Cg)alkyl, halo(Ci-Cg)alkoxy, C(0)R h , COOR h , C(0)NR h R i , 0-R ⁇ OC(0)R h , OC(0)NRV, NR h R', NR h C(0)R', NR h C(0)NR h R i , S(0) q (d- Cg)-alkyl,
- heterocyclyl is a 3- to 10-membered ring containing 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, S and O, wherein said heterocyclyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (Ci-Cg)-alkyl, (Ci-Cg)-alkoxy, (C 3 -Ci2)-cycloalkyl, (C6-C 10 )- aryl, heterocyclyl, heteroaryl, halo(C 1 -Cg)alkyl, halo(C 1 -Cg)alkoxy, C(0)R h , COOR h , C(0)NR h R i , 0-R ; , OC(0)R h , OC(0)NRV, NR h R ⁇ NR h C(0)R', NR h C(0)NR h R i , S(0) q (
- R h and R 1 are independently selected from the group consisting of hydrogen, (Ci-C 8 )-alkyl, (C 2 -C 8 )-alkenyl, halo(C 1 -C 8 )alkyl, (C3-C 12 )-cycloalkyl, (C 6 -C 10 )-aryl, (C 6 -C 10 )-aryl-(C 1 -C 8 )- alkyl, heteroaryl and heterocyclyl;
- substitution means that one or more hydrogen(s) of the specified moiety are replaced with a suitable substituent and includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and results in a stable compound.
- a refers to "one or more” when used in the subject specification, including the claims.
- reference to “a compound” may include a plurality of such compounds, or reference to “a disease” or “a disorder” includes a plurality of diseases or disorders.
- use of "(s)" as part of a term includes reference to the term singly or in plurality, e.g. the term compound(s) may indicate a single compound or more compounds.
- (Ci-C8)-alkyl refers to the radical of saturated aliphatic groups, including straight or branched-chain alkyl groups.
- a straight-chain or branched chain alkyl has eight or fewer carbon atoms in its backbone, for instance, Ci-C 8 for straight chain and C3-C8 for branched chain.
- (Ci-Cg)-alkyl refers to an alkyl group having 1 to 8 (both inclusive) carbon atoms; can preferably refer to an alkyl group having 1 to 6 (both inclusive) carbon atoms i.e.
- (Ci-Ce)-alkyl refers to an alkyl group having 1 to 4 (both inclusive) carbon atoms i.e. (Ci-C4)-alkyl.
- alkyl include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl and 3-methylbutyl.
- the alkyl group can be unsubstituted or substituted with one or more groups; preferably with 1-7 groups, more preferably with 1-3 groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (Ci-C 8 )- alkoxy, (C3-Ci2)-cycloalkyl, (Ce-Cio)-aryl, heterocyclyl, heteroaryl, halo(Ci-Cg)alkoxy, C(0)R h , OC(0)R h , COOR h , C(0)NR h R i , 0-R ⁇ OC(0)NR h R i , NR h R ⁇ NR h C(0)R i , NR h C(0)NR h R i , S(0) q (C 1 -C 8 )-alkyl, S(0) r NR h R i and NR h S(0) q R'; wherein R h and R h and R 1-3 groups
- (Ci-Cg)-alkylene refers to the corresponding bivalent radical of (C 1 -Cg)-alkyl group, including straight or branched-chain alkylene groups, and hence, the definition of (Cl-C8)alkyl group apply.
- Representative examples of alkylene include, but are not limited to, methylene, ethylene, n-propylene, n- butylene, n-pentylene, n-hexylene, n-heptylene, n-octylene, and isopropylene.
- the alkylene groups can be unsubstituted or substituted with one or more groups selected from the groups indicated above as the substituents for the corresponding alkyl group.
- halogen refers to a fluorine, chlorine, bromine, or iodine atom.
- halo(Ci-Cg)aikyi or “haloalkyl”, whether used alone or as part of a substituent group, refers to the alkyl group which is substituted with one or more halogens.
- a monohalo(Ci-Cg)aikyl radical for example, can have a chlorine, bromine, iodine or fluorine atom.
- Dihalo- or polyhalo(Ci-Cg)alkyl radicals can have two or more of the same or different halogen atoms.
- halo(Ci-Cg)alkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difiuoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl or the like groups.
- (C2-Cg)-alkenyl refers to a straight or branched chain hydrocarbon radical containing the indicated number of carbon atoms and at least one carbon-carbon double bond (two adjacent sp carbon atoms).
- (C2-Cg)-alkenyl refers to an alkenyl group having 2 to 8 (both inclusive) carbon atoms; preferably, can refer to alkenyl group having 2 to 6 (both inclusive) carbon atoms i.e.
- alkenyl can refer to alkenyl group having 2 to 4 (both inclusive) carbon atoms i.e. (C2-C4)-alkenyl.
- the geometry of the double bond may be
- E may be
- Z may be
- Representative examples of alkenyl include, but are not limited to, vinyl, allyl and 2-propenyl.
- the alkenyl groups can be unsubstituted or substituted with one or more groups.
- a substituted alkenyl refers to a (Ci-Cg)-alkenyl substituted with 1-7 groups, preferably with 1- 3 groups selected from the groups indicated above as the substituents for the alkyl group.
- (Ci-Cg)-alkoxy refers to a (Ci-Cg)-alkyl having an oxygen radical attached thereto.
- Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy.
- the alkoxy groups can be unsubstituted or substituted with one or more groups.
- a substituted alkoxy refers to a (Ci-Cg)-alkoxy substituted with 1-7 groups, preferably with 1-3 groups selected from the groups indicated above as the substituents for the alkyl group.
- halo(Ci-Cg)alkoxy or “haloalkoxy”, whether used alone or as part of a substituent group, refers to the alkoxy group which is substituted with one or more halogens.
- a monohalo(Ci-Cg)aikoxy radical for example, can have a chlorine, bromine, iodine or fluorine atom.
- Dihalo- or polyhalo(Ci-Cg)alkoxy radicals can have two or more of the same or different halogen atoms.
- halo(Ci-Cg)alkoxy include, but are not limited to, chloromethoxy, dichloromethoxy, trichloromethoxy, dichloroethoxy, dichloropropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy, difluoropropoxy or the like groups.
- (C3-Ci2)-cycloalkyl or "cycloalkyl”, whether used alone or as part of a substituent group, refers to a saturated cyclic hydrocarbon radical including 1, 2 or 3 rings including a total of 3 to 12 carbon atoms forming the rings, which can be unsubstituted or substituted with one or more substituents.
- cycloalkyl includes bridged, fused and spiro ring systems.
- (C3-Ci2)-cycloalkyl refers to a cycloalkyl group having 3 to 12 (both inclusive) carbon atoms; preferably, can refer to cycloalkyl group having 3 to 10 (both inclusive) carbon atoms i.e. (C3-Cio)-cycloalkyl; and more preferably, can refer to cycloalkyl group having 3 to 7 (both inclusive) carbon atoms i.e. (C3-C7)-cycloalkyl.
- cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, bicyclo[2.1.0]pentane, bicyclo[2.2.1]heptyl, and spiro[3.3]heptanes.
- (Cs-Cio)-cycloalkenyl or "cycloalkenyl”, whether used alone or as part of a substituent group, refers to a partially unsaturated monocyclic hydrocarbon radical containing a total of 5 to 10 carbon atoms forming the ring, which can be unsubstituted or substituted with one or more substituents.
- Representative examples of (C 3 ⁇ 4 - Cio)-cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexenyl, 1,2,3,3a- tetrahydropentalenyl and 1,2,3,4-tetrahydronaphthalenyl.
- the cycloalkyl or “the cycloalkenyl” group can be unsubstituted or substituted with one or more groups; preferably with 1-7 groups, more preferably with 1-3 groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (Ci-Cg)-alkyl, (Ci-Cg)-alkoxy, (C3-Ci2)-cycloalkyl, (C6-C 10 )- aryl, heterocyclyl, heteroaryl, halo(C Cg)alkyl, halo(d-Cg)alkoxy, C(0)R h , COOR h , C(0)NR h R i , 0-R ⁇ OC(0)R h , OC(0)NR h R ⁇ NR h R', NR h C(0)R', NR h C(0)NR h R i , S(0) q (d- C 8 )-alky
- (C6-Cio)-aryl or "aryl”, whether used alone or as part of a substituent group, refers to monocyclic or bicyclic hydrocarbon groups having 6 to 10 ring carbon atoms in which the carbocyclic ring(s) present have a conjugated pi electron system, which may be optionally substituted by one or more groups.
- Representative examples of (Ce-Cio)-aryl include, but are not limited to, phenyl or naphthyl.
- the aryl group can be unsubstituted or substituted with one or more groups.
- a substituted aryl refers to a (C6-Cio)-aryl substituted with one or more groups, preferably 1-7 groups and more preferably 1-3 groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (Ci-Cs)- alkyl, (Ci-Cg)-alkoxy, (C3-Ci2)-cycloalkyl, (Ce-Cio)-aryl, heterocyclyl, heteroaryl, halo(Ci- C 8 )alkyl, halo(C 1 -C 8 )alkoxy, C(0)R h , COOR h , C(0)NR h R ⁇ 0-R OC(0)R h , OC(0)NR h R i , NR h R ⁇ NR h C(0)R i , NR h C(0)NR h R
- (C6-Cio)-aryl-(Ci-Cg)-alkyl or "ar-(Ci-Cg)-alkyl” refers to an alkyl group substituted with an (Ce-Cio)-aryl group, wherein the terms alkyl and aryl are as defined above.
- Representative example of aralkyl group include (CH2) p -phenyl, wherein p is an integer from 1 to 6, such as benzyl wherein p is 1.
- the aryl of the (C6-Cio)-aralkyl group can be unsubstituted or substituted with groups selected from the groups indicated above as the substituents for the aryl group.
- heteroatom as used herein, includes nitrogen (N), oxygen (O) and sulfur (S). Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom to satisfy the valency.
- heterocyclyl or “heterocyclic”, whether used alone or as part of a substituent group, refers to a 3- to 10-membered saturated, partially unsaturated, monocyclic or bicyclic ring system containing 1 to 4 identical or different heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur.
- Saturated heterocyclic ring systems do not contain any double bond, whereas partially unsaturated heterocyclic ring systems, contain at least one double bond, but do not form an aromatic system containing a hetero atom.
- heterocyclyl include, but are not limited to, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, pyranyl, tetrahydropyranyl, pyrazinyl, piperazinyl, oxetanyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, thiazolyl, tetrazolyl, furyl, thienyl, purinyl, pyridinyl, pyridazinyl, pyrimidinyl, piperidyl, benzoxazolyl, benzothiazolyl, benzofuranyl, purinyl, benzimidazolyl, benzoxazolyl, indolyl, indazolyl, isoindolyl, isothiazolyl, isoquinolyl, mo holinyl, thiomorpholinyl, thiomo hol,
- the heterocyclyl group can be unsubstituted or substituted with one or more groups, preferably with 1-7 groups, more preferably with 1-3 groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (Ci-C8)-alkyl, (Ci-Cg)-aikoxy, (C3-Ci2)-cycloalkyl, (C6-Cio)-aryl, heterocyclyl, heteroaryl, halo(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkoxy, C(0)R h , COOR h , C(0)NRV, 0-R ⁇ OC(0)R h , OC(0)NR h R i , NR h R ⁇ NR h C(0)R', NR h C(0)NR h R i , S(0) q (C 1 -C 8 )-alkyl, S(0) r NR h
- heteroaryl refers to 5- to 10-membered heterocyclyl having an aromatic ring containing one to four identical or different hetero atoms selected from the group consisting of nitrogen, sulphur and oxygen atom.
- heteroaryl include, but are not limited to, pyrrole, pyrazole, imidazole, pyrazine, furan, thiophene, oxazole, oxadiazole, thiazole, benzimidazole, benzoxazole, benzothiazole, benzofuran, indole, indazole, isoindole, isoquinoline, isooxazole, triazine, purine, pyridine, quinoline, oxadiazole, thiene, pyridazine, pyrimidine, isothiazole, quinoxaline (benzopyrazine), tetrazole, pyrido[2,3-b]pyrazine.
- the oxidized form of the ring nitrogen and sulfur atom contained in the heteroaryl to provide the corresponding N-oxide, S-oxide or S,S-dioxide is also encompassed in the scope of the present invention.
- heteroaryl groups can be unsubstituted or substituted with one or more groups; preferably with 1-7 groups, more preferably with 1-3 groups selected from the groups indicated above as the substituents for the heterocyclyl group.
- isotopic forms or “isotopically labeled forms” is a general term used for isotopic forms of the compound of formula I, wherein one or more atoms of the compound of formula I are replaced by their respective isotopes. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the present invention. Examples of isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen such as 2 H (deuterium or D) and 3 H (tritium or T), carbon such as C, C and C, nitrogen such as N and N, oxygen such as O, O and
- isotopic forms of a compound of formula I can include, without limitation, deuterated compound of formula I.
- deuterated as used herein, by itself or used to modify a compound or group, refers to replacement of one or more hydrogen atom(s), which is attached to carbon(s), with a deuterium atom.
- the compounds of formula I can include in the definitions of one or more of its various variables, wherever applicable, deuterium, deuterated-alkyl, deuterated-alkoxy, deuterated-cycloalkyl, deuterated-aryl, deuterated-heterocyclyl, deuterated-heteroaryl and the like.
- deuterated-alkyl refers to (Ci-Cg)-alkyl group as defined herein, wherein at least one hydrogen atom bound to carbon is replaced by deuterium. That is, in a deuterated alkyl group, at least one carbon atom is bound to deuterium. In a deuterated alkyl group, it is possible for a carbon atom to be bound to more than one deuterium; it is also possible that more than one carbon atom in the alkyl group is bound to deuterium.
- deuterated and the terms deuterated-heterocyclyl, deuterated-heteroaryl, deuterated-cycloalkyl, deuterated-aryl and deuterated-alkoxy each refer to the corresponding chemical moiety wherein at least one carbon is bound to deuterium.
- solvate(s) refers to a compound formed by the interaction of a solute (in the present invention, a compound of formula I or a pharmaceutically acceptable salt thereof) and a solvent.
- solvents for the purpose of the invention may not interfere with the biological activity of the solute.
- the solvent used is a pharmaceutically acceptable solvent.
- suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid or a mixture thereof.
- the solvent used is water and the solvates obtained are referred to as hydrates.
- suitable solvates are the mono- or di- hydrates or alcoholates of the compounds of the present invention.
- stereoisomer or “stereoisomeric form” is a general term used for all isomers of individual compounds (in the present invention, a compound of formula I) that differ only in the orientation of their atoms in space.
- stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
- tautomer refers to the coexistence of two or more compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers or amide-imidic acid tautomers.
- the term "pharmaceutically acceptable” means that the carrier, diluent, excipient, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
- pharmaceutically acceptable salt(s) includes a salt or salts of the active compound i.e. the compound of formula I, which retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects; and are prepared using suitable acids or bases, depending on the particular substituents found on the compounds described herein.
- polymorph or “polymorphic form” refers to crystals of the same compound that differs only in the arrangement and/or conformation of the molecule (in the present invention, a compound of formula I) in the crystal lattice.
- N-oxide refers to the oxide of the nitrogen atom of a nitrogen-containing heteroaryl or heterocycle. N-oxide can be formed in the presence of an oxidizing agent such as m-chloroperbenzoic acid or hydrogen peroxide. N-oxide refers to an amine oxide, also known as amine-N-oxide, and is a chemical compound that contains N- ⁇ O bond.
- S-oxide refers to the oxide of the sulfur atom (S-oxide) or dioxide of the sulfur atom (S,S-dioxide) of a sulfur- containing heteroaryl or heterocycle.
- S-oxide and S, S-dioxides can be formed in the presence of an oxidizing agent for example, peroxide such as m-chloroperbenzoic acid or oxone.
- a prodrug or “prodrugs” refers to any compound, which are derivatives of a parent compound (in the context of the present invention, a compound of formula I), which following administration, release(s) the parent compound in vivo via a chemical or physiological process, e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the parent compound.
- the term "compound(s) of formula I" or “compounds of the present invention” are used interchangeably and unless indicated otherwise, includes all the isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, N-oxides and S-oxides thereof.
- the compound(s) of formula I can also be referred to herein as "the active compound” or "the active ingredient”.
- RORy refers to all isoforms encoded by the RORc gene which include RORyl and RORyt (RORy2).
- RORy modulator refers to an agent (in the context of the present invention, a compound of formula I) that modulates directly or indirectly the activity of RORy.
- RORy modulator is a compound which is capable of interacting, either directly or indirectly, with RORy receptor and initiates the pharmacological or biochemical response.
- RORy modulators include antagonist and inverse agonist of RORy.
- disease or disorder mediated by RORy refers to a disease or disorder in a subject caused due to the uncontrolled expression or dysfunction of the RORy or Th-17 cells.
- the diseases or disorders mediated by RORy can be selected from autoimmune diseases, inflammatory diseases, metabolic diseases, and cancer.
- therapeutically effective amount means an amount of a compound of formula I or a pharmaceutically acceptable salt thereof; or a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, effective in producing the desired therapeutic response in a particular patient (subject) suffering from a disease or disorder mediated by RORy such as an autoimmune disease, an inflammatory disease or a metabolic disease.
- therapeutically effective amount includes the amount of a compound (in the context of the present invention, the compound of Formula I or a pharmaceutically acceptable salt thereof), when administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to prevent development of, or alleviate to some extent one or more of the symptoms of the disease or disorder being treated in a subject.
- the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment.
- the therapeutically effective amount of the compound or composition will vary with the particular condition (in the context of the present invention, the disease or disorder that is mediated by RORy) being treated, the age and physical condition of the subject, the severity of the condition being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically acceptable carrier utilized and other related factors.
- the term "pharmaceutically acceptable carrier” refers to a material that is non-toxic, inert, solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary or excipient of any type which is suitable for a subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to the target site without affecting the activity of the agent.
- subject refers to an animal, preferably a mammal, and most preferably a human.
- mammal refers to warm-blooded vertebrate animals of the class 'mammalia' , including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
- mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human.
- subject may be used interchangeably with the term patient.
- the phrase "a subject in need thereof means a subject (patient) in need of the treatment for the disease or disorder that is mediated by RORy.
- the phrase "a subject in need thereof means a subject (patient) diagnosed having a disease or disorder that is mediated by RORy.
- treatment means to alleviate, slow the progression, attenuation, prophylaxis or as such treat the existing diseases or condition (e.g. autoimmune, inflammatory or metabolic diseases). Treatment also includes treating, preventing development of, or alleviating to some extent, one or more of the symptoms of the diseases or condition.
- the present invention relates to a compound of formula I;
- R 1 is -S(0) m R a , -S(0) r NR b R c , -S(0) r (NR b )R a , -NR b COR c , -NR b S(0) m R a or -NR b S(0) r NR b R c ;
- R a , R b , R c , r and m are as defined in the first aspect of the invention.
- 1 is -S(0) r NR b R c , wherein R b and R c can combine to form a saturated or
- the present invention relates to a compound of formula I, wherein: R d , R e , X and n are as defined in the first aspect of the invention;
- the present invention relates to a compound of formula I, wherein: R 1 is -S(0) m R a , -S(0) r NR b R c or -S(0) r (NR b )R a ;
- R a , R b , R c , r and m are as defined in the first aspect of the invention.
- the present invention relates to a compound of formula I, wherein: R 1 is -NR b COR c , -NR b S(0) m R a or -NR b S(0) r NR b R c ;
- R a , R b , R c , m and r are as defined in first aspect of the invention.
- R 1 is NR b COR c , wherein R b is hydrogen and R c is (Ci-Cg)-alkyl, then Q is ; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof.
- the present invention relates to a compound of formula I, wherein: L is -CO-;
- the present invention relates to a compound of formula I, wherein: L is -S(0)2-;
- the present invention relates to a compound of formula I, wherein: A is wherein R 5 , R 6 , R 7 , c and Q are as defined in the first aspect of the invention;
- the present invention relates to a compound of formula I, wherein: A i
- R , T, Q and d are as defined in the first aspect of the invention.
- the present invention relates to a compound of formula I, wherein: Q is
- R , R x and e are as defined in the first aspect of the invention.
- the present invention relates to a compound of formula I, wherein: Q is
- R , R y , o and s are as defined in the first aspect of the invention.
- the present invention relates to a compound of formula I, wherein: Q is
- R x , R 11 , X 1 , X 2 , X 3 , X 4 , X 5 , t, e and s are as defined in the first aspect of the invention; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof.
- the present invention relates to a compound of formula I, wherein: Q is
- R is as defined in the first aspect of the invention.
- the present invention relates to a compound of formula I, wherein: A is
- R 5 , R 6 , R 7 , R 9 , R x , c and e are as defined in the first aspect of the invention.
- the present invention relates to a compound of formula I, wherein: A is
- R 5 , R 6 , R 7 , R x , R y , X 1 , X 2 , c, e, t and s are as defined in the first aspect of the invention
- the present invention relates to a compound of formula I, wherein:
- R 1 is -S(0) m R a ;
- X 1 is CR 12 R 13
- X 2 is CR 14 R 15
- R 14 and R 15 are hydrogen
- R a , R 5 , R 6 , R 7 , R 12 , R 13 , R x , R y , c, e, m, t and s are as defined in the first aspect of the invention
- the present invention relates to a compound of formula I, wherein:
- R 1 is -S(0) m R a ;
- L is -CO-
- X 1 is CR 12 R 13
- X 2 is CR 14 R 15
- R 14 and R 15 are hydrogen
- R a , R 5 , R 6 , R 7 , R 12 , R 13 , R x , R y , m, c, e, t and s are as defined in the first aspect of the invention
- Representative compounds of formula I encompassed in accordance with the present invention include:
- the compounds of the present invention include all isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, prodrugs, N-oxides, S-oxides and polymorphs.
- the compound(s) of formula I can be prepared by various methods including using methods well known to a person skilled in the art. Examples of processes for the preparation of a compound of formula I are described below and illustrated in the following scheme, but are not limited thereto. It will be appreciated by persons skilled in the art that within certain of the processes described herein, the order of the synthetic steps employed can be varied and will depend inter alia on factors such as the nature of functional groups present in a particular substrate and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagents such as bases, solvents, coupling agents to be used in the reaction steps. The reagents, reactants and intermediates used in the following processes are either commercially available or can be prepared according to standard procedures known in the art, for instance those reported in the literature references.
- Scheme 1 depicts a general reaction scheme for the preparation of the compound of formula I
- an appropriate amine represented by the compound of formula B-2 is coupled with an appropriately substituted acetic acid represented by the compound of formula B-1, using a suitable coupling reagent, such as 1- emyl-3-(3-dimethylaminopropyl)carbodiirnide (EDC.HC1), 2-(7-aza-lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), hydroxybenzotriazole (HOBt), oxalyl chloride and the like; in presence of a suitable solvent such as N,N- dimethylformamide (DMF), dichlorome thane (DCM), tetrahydrofuran (THF) and the like optionally in the presence of a base such as N,N-diisopropylethylamine (DIEA), triethylamine (TEA) and the like; to obtain
- a suitable solvent such as N,N-di
- An appropriate amine represented by the compound of formula B-2 is coupled with an appropriately substituted phenylacetic acid represented by the compound of formula B-3 using a suitable coupling reagent, such as EDC.HCl, HATU, HOBt, oxalyl chloride and the like; in the presence of a suitable solvent such as DMF, DCM, THF and the like; optionally in the presence of a base such A, TEA and the like; to obtain the compound of formula
- Step 2 The compound of formula B-4 obtained in the step 1 is reacted with iron powder and ammonium chloride in the presence of a mixture of solvents such as ethanol:water:THF at a temperature ranging from 60 °C to 80 °C for 5-6 hours to obtain the compound of formula
- the compounds of formula I can be converted into their pharmaceutically acceptable salts.
- the present invention also includes within its scope the pharmaceutically acceptable salts of the compounds of formula I.
- pharmaceutically acceptable salts refers to organic and inorganic salts of a compound of the present invention (the compounds of formula I), depending on the particular group (acidic or basic group) present in the said compounds.
- base addition salts can be obtained by contacting the compounds of formula I with a sufficient amount of an appropriate base, either neat or in a suitable inert solvent.
- pharmaceutically acceptable base addition salts include sodium, potassium, calcium, magnesium, ammonium salts; or an organic base salt.
- pharmaceutically acceptable organic base addition salts include those derived from organic bases such as lysine, arginine, guanidine, diethanolamine, choline, tromethamine and the like.
- acid addition salts can be obtained by contacting the compound of formula I with a sufficient amount of an appropriate acid, either neat or in a suitable inert solvent.
- pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, mono-hydrogensulfuric or hydroiodic acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, glucuronic or galacturonic acids and the like.
- Certain specific compounds of the present invention contain both basic and acidic functionalities that
- the compound of formula I can be regenerated from their corresponding salts by contacting the said salt with an appropriate base or acid depending on the type of salt and isolating the parent compound in the conventional manner.
- the corresponding salts of the compounds differ from their parent compounds with respect to certain physical properties, for example solubility.
- the present invention also encompasses within its scope the solvates of the compounds of formula I.
- Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are suitable for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
- polymorphs of the compounds of formula I can be prepared by crystallization of the compounds under different conditions.
- the different conditions are, for example, using different solvents or their mixtures for crystallization; crystallization at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations.
- Polymorphs can also be obtained by heating or melting the compound followed by gradual or fast cooling.
- the presence of polymorphs can be determined by infrared (IR) spectroscopy, solid probe nuclear magnetic resonance (NMR) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
- the present invention includes all possible stereoisomers and geometric isomers of the compound of formula I and includes not only racemic compounds but also the optically active isomers as well.
- a compound of formula I When a compound of formula I is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or an appropriate intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art, for example, Chiral reagents for asymmetric synthesis by Leo A. Paquette; John Wiley & Sons Ltd (2003).
- the present invention is intended to include all tautomeric forms of the compounds.
- prodrugs of the compound(s) of formula I are those compounds that are converted intracellularly, more preferably, where the cellular converting location is the site of therapeutic action.
- preferred produgs are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid.
- pharmaceutically acceptable esters include lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters such as the pivaloyloxymethyl ester and the like esters which are conventionally known in the art.
- the present invention relates to pharmaceutical compositions that contain a therapeutically effective amount of at least one compound of formula I or its pharmaceutically acceptable salt in addition to a customary pharmaceutically acceptable carrier or excipient.
- the present invention also relates to a process for the production of the pharmaceutical composition, which includes bringing at least one compound of formula I, into a suitable administration form using a pharmaceutically acceptable excipient or a carrier and, if appropriate, further suitable a pharmaceutically acceptable carriers, additives or auxiliaries.
- the pharmaceutical compositions containing the compounds of Formula I according to the invention are prepared in a manner known to one skilled in the art.
- compositions can be administered orally, for example in the form of pills, tablets, coated tablets, capsules, granules or elixirs. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermally, in the form of patches, or in other ways, for example in the form of aerosols or nasal sprays.
- oral dosages form of the compounds of Formula I such as the pills, tablets, coated tablets and hard gelatin capsules
- lactose corn starch or derivatives thereof, gum arabica, magnesia or glucose
- Pharmaceutically acceptable carriers that can be used for soft gelatin capsules and suppositories are, for example, fats, waxes, natural or hardened oils, etc.
- Suitable pharmaceutically acceptable carriers for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the said solvents.
- the pharmaceutical compositions can contain from about 1 % to 99 , for example, about 5 % to 70 , or from about 10 % to about 30 % by weight of the compound of formula I or its pharmaceutically acceptable salt.
- the amount of the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical compositions normally is from about 5 mg to 500 mg or may be lower than or higher than the lower and the upper limit respectively.
- the dose of the compound of formula I, which is to be administered can cover a wide range depending on the type of disease or disorder to be treated. The dose to be administered daily is to be selected to have the desired effect.
- a suitable dosage can be from about 0.01 mg/kg to 100 mg/kg of the compound of formula I or its pharmaceutically acceptable salt depending on the body weight of the recipient (subject) per day, for example, from about 0.1 mg/kg to 50 mg/kg/day of a compound of formula I or a pharmaceutically acceptable salt of the compound. If required, higher or lower daily doses can also be administered.
- the selected dosage level will depend upon a variety of factors including the activity of a compound of the present invention, or its salt employed, the route of administration, the time of administration, the rate of excretion of the particular compound being administered, the duration of the treatment, other concurrently administered drugs, compounds and/or materials, the age, sex, weight, condition, general health and prior medical history of the patient (subject) being treated, and like factors well known in the medical arts.
- the pharmaceutical compositions of the present invention can contain additives such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers, flavors, preservatives, solubilizers or colorants. They can also contain more than one compound of formula I or their pharmaceutically acceptable salts. Furthermore, in addition to at least one compound of formula I or its pharmaceutically acceptable salt, the pharmaceutical compositions can also contain one or more other therapeutically or prophylactically active agents.
- the present invention relates to a method for the treatment of a disease or a disorder mediated by RORy, comprising administering to a subject in need thereof; a therapeutically effective amount of a compound of formula I or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
- the present invention provides use of a compound of formula I or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof; for the treatment of a disease or a disorder mediated by RORy
- the present invention provides use of a compound of formula I or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment of a disease or a disorder mediated by RORy
- the disease or disorder mediated by RORy is an autoimmune disease/disorder, an inflammatory disorder or a metabolic diseases/disorder.
- the disease or disorder mediated by RORy is cancer.
- the disease or disorder mediated by RORy is an autoimmune disease or disorder.
- the disease or disorder mediated by RORy is an inflammatory disorder.
- the disease or disorder mediated by RORy is a metabolic disease or disorder.
- the disease or disorders mediated by RORy is selected from respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD) and bronchitis; allergic diseases such as allergic rhinitis and atopic dermatitis; arthritis; multiple sclerosis; psoriasis; cystic fibrosis; lung allograph rejection, Crohn's disease, inflammatory bowel diseases (IBD); irritable bowel syndrome (IBS); colitis and ulcerative colitis.
- respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD) and bronchitis
- allergic diseases such as allergic rhinitis and atopic dermatitis
- arthritis multiple sclerosis
- psoriasis cystic fibrosis
- lung allograph rejection Crohn's disease
- IBD inflammatory bowel diseases
- IBS irritable bowel syndrome
- the disease or disorders mediated by RORy is an autoimmune diseases/disorder or an inflammatory disease/disorder; which can be selected from the group consisting of: inflammatory bowel disease, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non-rheumatoid arthritis, ankylosing spondylitis, osteoporosis/bone resorption, chronic graft-versus-host disease, acute graft-versus-host disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren's syndrome, scleroderma, asthma, bronchitis, epidermal hyperplasia, Crohn's disease, atherosclerosis, septic shock syndrome, coronary fibrosis,
- autoimmune disease that can be treated by the compound of present invention is selected from alopecia areata, autoimmune hemolytic anemia, autoimmune hepatitis, dermatomyositis, diabetes (type 1), some forms of juvenile idiopathic arthritis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, some forms of myocarditis, multiple sclerosis, pemphigus/pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma/systemic sclerosis, Sjogren's syndrome, systemic lupus erythematosus, Pernicious anemia (Addison's disease), some forms of thyroiditis (Hashimoto's thyroid
- the inflammatory disorders are selected from the group consisting of arthritis, asthma, atherosclerosis, celiac disease, chronic prostatitis, colitis, Crohn's disease, dermatitis, diverticulitis, glomerulonephritis, hepatitis, hypersensitivities, inflammatory bowel diseases (IBD), interstitial cystitis, irritable bowel syndrome (IBS), lupus erythematous, nephritis, Parkinson's disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, ulcerative colitis and vasculitis.
- IBD inflammatory bowel diseases
- IBS irritable bowel syndrome
- lupus erythematous nephritis
- Parkinson's disease pelvic inflammatory disease
- reperfusion injury rheumatoid arthritis
- sarcoidosis transplant rejection
- ulcerative colitis and vasculitis vasculitis
- the cancers include, but are not limited to, thyroid carcinoma, cardiac sarcoma, lung carcinoma, gastrointestinal carcinoma, genitourinary tract carcinoma, liver carcinoma, mantle cell lymphoma, bone sarcoma, sarcoma of the nervous system, gynaecological carcinoma, haematological cancer, adrenal gland neuroblastoma, skin cancer, astrocytic cancer, breast cancer, colorectal cancer, endometrial cancer, head and neck cancer and oral cancer.
- the arthritis that can be treated by the compound of present invention includes rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, gouty arthritis, pseudogout arthritis, lupus arthritis, septic arthritis and spondyloarthropathies (ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthritis and enteropathic arthritis).
- the present invention also encompasses within its scope use of a compound of formula I or a stereisomer, a tautomer or a pharmaceutically acceptable salt thereof; in combination, with other therapeutically active agents; wherein the compound of formula I and the further therapeutic agent are administered either simultaneously or sequentially.
- the therapeutically active agents used in combination with one or more compounds of formula I or its pharmaceutically acceptable salt can be selected from P2-adrenoreceptor agonists (for example, but not limited to, bambuterol, formoterol, levosalbutamol, salmeterol and salbutamol), S1P1 agonist (for example, but not limited to, fingolimod, siponimod (phase III, Novartis) and RPC-1063 (phase III, Receptos)), Hj receptor antagonist, antiinflammatory agents (e.g.
- corticosteroids for example, fluticasone
- non-steroidal antiinflammatory agent for example, but not limited to, diclofenac, indomethacin, sulindac, mefenamic acid, piroxicam, ibuprofen, naproxen, ketoprofen, phenylbutazone, aspirin, diflunisal, nimesulide, celecoxib, valdecoxib, etorcoxib and meloxicam)
- anticholinergic agents for example, but not limited to, ipratropium, tiotropium and oxitropium
- anti-diabetic agents for example, but not limited to alogliptin, anagliptin, sitagliptin, saxagliptin, vildagliptin, denagliptin, Dutogliptin, Teneligliptin, Trelagliptin (SYR-472, phase III), ge
- Methyl 2-(4-aminophenyl)acetate (1.0 g, 6.05 mmol) was refluxed in trimethoxymethane (6.42 g, 60.5 mmol) for 6 hours.
- the solvent was evaporated and re-dissolved in methanol (10 mL) and added sodium borohyride (0.275 g, 7.26 mmol) at 0 °C.
- the reaction mixture was stirred at RT for 3 hours.
- the solvent in the reaction mixture was distilled off; the residue was acidified with dilute HC1 and extracted with ethyl acetate. Reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL).
- Step 3 2-(4-(Aminomethyl)phenyl)-l,l,l,3,3,3-hexafluoropropan-2-ol
- Step 1 l-(4-Nitrophenyl)cyclopropanecarbonitrile
- Step 2 l-(4-Aminophenyl) cyclopropanecarbonitrile
- ethanol 15 mL
- water 5 mL
- iron 1484 mg, 26.6 mmol
- ammonium chloride 1421 mg, 26.6 mmol
- the reaction mixture was heated at 80 °C for 2 hours.
- the reaction mixture was filtered through celite bed and the residue was washed with ethanol.
- the filtrate was evaporated to remove the solvent, added water and extracted with ethyl acetate.
- the organic layer was dried over sodium sulphate and evaporated to obtain crude material.
- the crude material was purified by column chromatography (silica gel, hexane and ethyl acetate).
- Step 1 4,4,5,5-Tetramethyl-2-(4-nitro-2-(trifluoromethyl)phenyl)-l,3,2-dioxaborolane
- l-bromo-4-nitro-2-(trifluoromethyl)benzene 5.0 g, 18.52 mmol
- 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (4.70 g, 18.52 mmol) in dioxane (50 mL)
- potassium acetate 2.73 g, 27.8 mmol
- [l,l-bis(diphenylphosphino)ferrocene]dichloro palladium (I) complex with DCM 0.756 g, 0.926 mmol
- reaction mixture was refluxed for 16 hours and cooled the reaction mixture to RT.
- the reaction mixture was filtered through celite, filtrate was concentrated and purified by column chromatography (silica gel, hexane and ethyl acetate) to obtain the title compound.
- Step 3 4 , -Nitro-2 , -(trifluoromethyl)-5,6-dihydro-[l,l'-biphenyl]-4(3H)-one
- Step 4 4'-Amino-2'-(trifluoromethyl)-5,6-dihydro-[l,l'-biphenyl]-4(3H)-one
- Step 2 4-Ethyl-7-nitro-2H-benzo[b][l,4]oxazin-3(4H)-one
- cesium carbonate (2.52 g, 7.73 mmol)
- 7-nitro-2H- benzo[b][l,4]oxazin-3(4H)-one (1 g, 5.15 mmol) in DMF (5 mL)
- ethyl iodide 0.99 mL, 6.18 mmol
- This compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)acetic acid (70.2 mg, 0.308 mmol) and 6-aminothiochroman-4-one 1,1-dioxide (Intermediate 1-7, 65 mg, 0.308 mmol) using HATU (234 mg, 0.615 mmol) and DIEA (0.161 mL, 0.923 mmol) in DMF (3 mL) as per the process described in the preparation of the compound of example 1.
- This compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)acetic acid (191 mg, 0.837 mmol) with 6-aminothiochroman-4-one (Intermediate 1-8, 150 mg, 0.837 mmol) using HATU (636 mg, 1.674 mmol), DIEA (0.438 mL, 2.51 mmol) in dry THF as per the process described for the preparation of the compound of example 1.
- This compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)acetic acid (167 mg, 0.733 mmol) with 2-(2-amino-5-cyclohexylphenyl)-l,l,l,3,3,3-hexafluoropropan-2-ol (Intermediate I- 10, 0.249 g, 0.733 mmol) using HATU (557 mg, 1.465 mmol), DIEA (0.384 mL, 2.198 mmol) in DMF (6 mL) as per the process described for the preparation of the compound of example 1.
- This compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)acetic acid (100 mg, 0.438 mmol) with l-(4-aminophenyl)cyclopropanecarbonitrile (Intermediate I-l l, 62.4 mg, 0.394 mmol) using the HATU (333 mg, 0.876 mmol), DIEA (230 ⁇ ,, 1.314 mmol) in DMF (6 mL) as per the process described in the preparation of the compound of example 1.
- This compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)acetic acid (0.2 g, 0.87 mmol) with 4-(l , l ,l ,3,3,3-hexafluoro-2-(4-phenylbutoxy)propan-2-yl)aniline (0.17 g, 0.438 mmol) using HATU (0.33 g, 0.876 mmol) and DIEA (0.11 g, 0.876 mmol) as described for the preparation of the compound of example 1.
- This compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)acetic acid (0.1 g, 0.438 mmol) with 2-(4-amino-3-methylphenyl)-l , l, l,3,3,3-hexafluoropropan-2-ol (0.12 g, 0.438 mmol) using HATU (0.33 g, 0.876 mmol) and DIEA (0.11 g, 0.876 mmol) as per the process described for the preparation of the compound of example 1.
- This compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl) acetic acid (0.100 g, 0.438 mmol) with 2-(4-amino-3-methylphenyl)-l ,l , l ,3,3,3-hexafluoropropan-2-ol (0.12 g, 0.438 mmol) using HATU (0.33 g, 0.876 mmol) and DIEA (0.11 g, 0.876 mmol) as per the process described for the preparation of the compound of example 1.
- This compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl) acetic acid (0.100 g, 0.438 mmol) with 2-(4-aminophenyl)-l,l,l-trifluoropropan-2-ol (0.09g, 0.438 mmol) using HATU (0.33 g, 0.876 mmol) and DIEA (0.11 g, 0.876 mmol) as per the process described for the preparation of the compound of example 1.
- the title compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)acetic acid (0.100 g, 0.438 mmol) with l-(4-aminophenyl)-2,2,2-trifluoroethanol (0.084 g, 0.438 mmol) using HATU (0.33 g, 0.876 mmol) and DIEA (0.11 g, 0.876 mmol) as per the process described for the preparation of the compound of example 1.
- the title compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)acetic acid (0.100 g, 0.438 mmol) with 4-(2-(2-cyclohexylethoxy)-l,l,l,3,3,3-hexafluoropropan-2- yl)aniline (0.162 g, 0.438 mmol) using HATU (0.33 g, 0.876 mmol) and DIEA (0.11 g, 0.876 mmol) as per the process analogous to the preparation of the compound of example 1.
- the title compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)acetic acid (0.100 g, 0.438 mmol) with 4-(l,l,l,3,3,3-hexafluoro-2-(2-(piperidin-l-yl)ethoxy)propan-2- yl)aniline (0.16 g, 0.438 mmol) using HATU (0.33 g, 0.876 mmol) and DIEA (0.11 g, 0.876 mmol) as per the process described for the preparation of the compound of example 1.
- the title compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)acetic acid (0.200 g, 0.876 mmol) with 2-(4-aminophenyl)-l,l, l,3,3,3-hexafluoropropan-2-ol (0.227 g, 0.876 mmol) using HATU (0.66 g, 1.75 mmol) and DIEA (0.22 g, 1.75 mmol) as per the process described for the preparation of the compound of example 1.
- the title compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)acetic acid (0.200 g, 0.876 mmol) with l, l,l,3,3,3-hexafluoro-2-(4-(piperazin-l-yl)phenyl)propan-2-ol (0.287 g, 0.876 mmol) using HATU (0.66 g, 1.75 mmol) and DIEA (0.22 g, 1.75 mmol) as per the process described for the preparation of the compound of example 1.
- the title compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)acetic acid (1.0 g, 4.38 mmol) with 6-amino-3,4-dihydronaphthalen-l(2H)-one (0.70 g, 4.38 mmol) in the presence HATU (3.33 g, 8.76 mmol), DIEA (1.13 g, 8.76 mmol) as per the process described for the preparation of the compound of example 1.
- the title compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)acetic acid (0.124 g, 0.543 mmol) with 5,6,7,8-tetrahydronaphthalen-2-amine (0.080 g, 0.544 mmol) using HATU (0.413 g, 1.08 mmol) and DIEA (0.140 g, 1.0 mmol) as per the process described for preparation of the compound of example 1.
- the title compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)acetic acid (0.1 g, 0.43 mmol) with 2-(4-aminophenyl)-2-methylpropanenitrile (0.070 g, 0.438 mmol) using oxalyl chloride (0.067 g, 0.826 mmol) and TEA (0.067 g, 0.52mmol) as per the process described for the preparation of the compound of example 1.
- the title compound was prepared analogous to the process described in example 1 by the reaction of 2-(3-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-l,l,l,3,3,3-hexafluoropropan-2-ol with 2-(4-(ethylsulfonyl)phenyl)acetic acid.
- This compound was prepared by the reaction of 2-(4-(2-oxopyrrolidin-l-yl)phenyl)acetic acid (1-2) with 2-(4-aminophenyl)-l,l,l,3,3,3-hexafluoropropan-2-ol (220 mg, 0.860 mmol) using EDC (200 mg, 1.03 mmol), HOBt (130 mg, 0.86 mmol) in dry DCM (5 mL) as per the process described for the preparation of the compound of example 19.
- This compound was prepared by the reaction of 2-(4-acetamidophenyl)acetic acid (1-3, 0.10 g, 0.52 mmol) with 2-(4-aminophenyl)-l, 1, 1, 3, 3, 3-hexafluoropropan-2-ol (0.13 g, 0.52 mmol) using EDC.HC1 (0.12 g, 0.62 mmol), HOBt (0.08 g, 0.52 mmol) in dry DCM (5 mL) as per the process described for the preparation of the compound of example 19.
- This compound was prepared by the reaction of 2-(4-(N-methylpivalamido)phenyl)acetic acid (1-4, 0.05 g, 0.20 mmol) with 2-(4-aminophenyl)-l, 1, 1, 3, 3, 3-hexafluoropropan-2-ol (0.05 g, 0.20 mmol) using EDC (0.05 g, 0.24 mmol), HOBt (0.03 g, 0.20 mmol) in dry DCM (4 mL) as per the process described for the preparation of the compound of example 19.
- This compound was prepared by the reaction of 4-(cyclohexyloxy)-3-(trifluoromethyl)aniline (1-5, 40 mg, 0.15 mmol) with 2-(4-(ethylsulfonyl) phenyl) acetic acid (30 mg, 0.15 mmol) using EDC.HC1 (30 mg, 0.18 mmol), lH-benzo[d] [l,2,3]triazol-l-ol (77 mg, 0.15 mmol) in DCM (4 mL) as per the process described for the preparation of the compound of example 19.
- This compound was prepared by the reaction of 4'-amino-2'-(trifluoromethyl)-5,6-dihydro- [l,l'-biphenyl]-4(3H)-one (1-12, 80 mg, 0.313 mmol) with 2-(4-(ethylsulfonyl)phenyl)acetic acid (71.5 mg, 0.313 mmol) using EDC.HC1 (71.8 mg, 0.376 mmol), HOBt (42.4 mg, 0.313 mmol) in DCM (4 mL) as per the process described for the preparation of the compound of example 19.
- the title compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)acetic acid (130 mg, 0.571 mmol) and 4-phenylcyclohexanamine (100 mg, 0.571 mmol) in presence of EDC.HC1 (131 mg, 0.685 mmol) and HOBt (77 mg, 0.571 mmol) analogous to the process described for the preparation of the compound of example 19.
- This compound was prepared by the reaction of 2-(4-(morpholinosulfonyl)phenyl)acetic acid (1-9, 75 mg, 0.263 mmol) with 2-(4-aminophenyl)-l,l,l,3,3,3-hexafluoropropan-2-ol (68.1 mg, 0.263 mmol) using EDC.HCl (76 mg, 0.394 mmol), HOBt (60.4 mg, 0.394 mmol) and DIEA (0.092 mL, 0.526 mmol) in DCM (5 mL) as per the process described for the preparation of the compound of example 26.
- This compound was prepared by the reaction of 5-cyclohexylidene-5, 6,7,8- tetrahydronaphthalen-2-amine (1-13, 0.2 g, 0.880 mmol) with 2-(4- (ethylsulfonyl)phenyl)acetic acid (0.201 g, 0.880 mmol) using EDC.HCl (0.205 g, 1.320 mmol), HOBt (0.202 g, 1.320 mmol), DIEA (0.154 mL, 0.880 mmol) in anhydrous THF as per the process described for the preparation of the compound of example 26.
- This compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl) acetic acid (1.119 g, 4.90 mmol) with 6-aminochroman-4-one (1-14, 0.8 g, 4.90 mmol) using EDC.HCl (1.410 g, 7.35 mmol), HOBt (1.126 g, 7.35 mmol) and DIEA (2.141 mL, 12.26 mmol) in dry THF (20 mL) as per the process described for the preparation of the compound of example 26.
- the title compound was prepared by the reaction of 2-(4-aminophenyl)-l, 1,1,3, 3,3- hexafluoropropan-2-ol (0.062 g, 0.240 mmol) with 2-(thiochroman-6-yl)acetic acid (0.05 g, 0.240 mmol) using EDC.HCl (0.69 g, 0.36 mmol), HOBt (0.55 g, 0.360 mmol) and DIPEA (0.210 mL, 1.2 mmol) as per the process described for the preparation of the compound of example 26.
- the title compound was prepared analogous to the process described in example 26 by the reaction of 7-amino-4-(4-methoxybenzyl)-2H-benzo[b] [l,4]oxazin-3(4H)-one with 2-(4- (ethylsulfonyl)phenyl)acetic acid.
- Step 1 N-(4-Benzoylphenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide
- This compound was prepared by the reaction of (4-aminophenyl)(phenyl)methanone (1 g, 5.07 mmol) with 2-(4-(ethylsulfonyl)phenyl)acetic acid (1.157 g, 5.07 mmol) using EDC.HCl (1.162 g, 6.08 mmol), HOBt (0.685 g, 5.07 mmol)in DCM (15 mL) as per the process described for the preparation of the compound of example 19.
- N-(4-Benzoylphenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide (0.100 g, 0.25 mmol), as obtained in step 1 , was stirred in dry THF (5 mL) at 0 °C under nitrogen atmosphere. To this was added methyl magnesium bromide (0.12 g, 1.0 mmol) drop wise and the reaction mixture was stirred at RT for 12 hours. The reaction mixture was quenched with saturated ammonium chloride solution (2 mL), and extracted with ethyl acetate (10 mL).
- the title compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)-N-(5-oxo- 5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (Example 15, 0.250 g, 0.673 mmol) with phenylmagnesium bromide (2.69 mL, 2.69 mmol) as per the process described for the preparation of the compound of example 41.
- the title compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)-N-(5-oxo- 5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (Example 15, 1.0 g, 2.69 mmol) with p- methoxyphenylmagnesium bromide (21.54 mL, 10.77 mmol) as per the process described for the preparation of the compound of example 41.
- the title compound was prepared by the reaction of 2-(4-(ethylsulfonyl)phenyl)-N-(5-oxo- 5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (Example 15, 0.2 g, 0.538 mmol) and allylmagnes-ium bromide (4.31 mL, 2.15 mmol) as per the process described for the preparation of the compound of example 41.
- Step 1 N-(4-(l,l,l,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)phenyl)-2-(4-nitrophenyl) acetamide
- Step 2 2-(4-Aminophenyl)-N-(4-(l,l,l,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl) acetamide
- ethanol 6 mL:water (4 mL):THF (2 mL)
- iron powder 0.132 g, 2.368 mmol
- ammonium chloride 0.127 g, 2.36 mmol
- Step 3 2-(4-(Ethylsulfonamido)phenyl)-N-(4-(l,l,l,3,3,3-hexafluoro-2-hydroxypropan- 2-yl)phenyl)acetamide
- This compound was prepared by the reaction of 2-(4-aminophenyl)-N-(4-(l, 1,1,3, 3,3- hexafluoro-2-hydroxypropan-2-yl)phenyl)acetamide (0.08 g, 0.209 mmol) with 4-(trifluoro methyl)benzene-l-sulfonyl chloride (0.061 g, 0.251 mmol) using pyridine (0.081 mL, 1.045 mmol) analogous to the process described in step 3 of the preparation of the compound of example 45.
- Step 1 To the stirred solution of 2-(4-(ethylsulfinyl)phenyl)acetic acid (0.120g, 0.565 mmol) in dry DCM (10 mL), was added Nl-((ethylimino)methylene)-N3,N3-dimethylpropane-l,3- diamine, HC1 salt (0.108 g, 0.565 mmol), 2-(3-aminophenyl)-l,l,l,3,3,3-hexafluoropropan-2- ol (0.147 g, 0.565 mmol)and lH-benzo[d][l,2,3]triazol-l-ol salt (0.087 g, 0.565 mmol) under inert atmosphere. The reaction continued overnight.TLC showed completion of the reaction. Solvent was evaporated and crude residue was used further.
- Step 2 To 110 mg of 2-(4-(ethylsulfinyl)phenyl)-N-(3-(l,l,l,3,3,3-hexafluoro-2- hydroxypropan-2-yl)phenyl)acetamide, was added chloroform and cooled to 0-5 °C. Sodium azide (2.0eqiv.) was added followed by addition of 2.0 eqiv. of sulphuric acid dropwise. The reaction mixture was stirred overnight. The chloroform layer was decanted. The reaction mass was neutralised with sodium bicarbonate and extracted with DCM, dried over sodium sulphate and solvent was removed under reduced pressure. Crude residue was further purified on column to afford pure desired product.
- Step 1 To the stirred solution of 2-(4-(ethylsulfonyl) phenyl)-N-(4-(l, l,l,3,3,3-hexafluoro-2- hydroxypropan-2-yl)phenyl)acetamide (lequiv.) in dry THF, was added methanesulfonyl chloride ( 1 equiv.) followed by triethyl amine (2 equiv.) at 0°C. The resulting reaction mixture was stirred for another 3-4 hours. Completion of reaction was monitored by TLC and solvent was removed under vacuum. The residue was diluted with water and extracted with ethylacetate several times. The combined organic layer was washed with brine dried over anhydrous Na 2 S0 4 and solvent was evaporated under vacuum. Crude residue was used without further purification.
- Step 2 To the stirred solution of 2-(4-(2-(4-(ethylsulfonyl)phenyl)acetamido)phenyl)- l,l,l,3,3,3-hexafluoropropan-2-yl methanesulfonate (O. lOOg, 0.183 mmol) in acetonitrile (dry) under inert atmosphere, was added potassium carbonate (0.050 g, 0.365 mmol), followed by respective nucleophiles (0.183 mmol). The reaction mixture was then heated to reflux for 3 hours. Completion of the reaction was monitored by TLC. Excess solvent was removed and diluted with DCM. The organic layer was washed with water and brine and purified by column chromatography to afford pure product.
- Step-1 To a stirred solution of 4-nitrobenzoyl chloride (1.0 g, 5.39 mmol) and phenylboronic acid in THF (0.657 g, 5.39 mmol) in toluene, was added K 2 C0 3 (1.862 g, 13.47 mmol) followed by Pd(Ph 3 P) 4 (0.016 g, 0.054 mmol). The reaction mixture was heated to reflux for 16 hours and brought to room temperature. The solvent was evaporated under pressure and crude compound was purified on column chromatography.
- Step-2 To a stirred solution of (4-nitrophenyl)(phenyl)methanone (1.0 g, 4.40 mmol) and trimethyl(trifluoromethyl)silane (0.782 mL, 5.28 mmol) in DMF was added K 2 C0 3 (0.061 g, 0.440 mmol) and stirred at RT for 3 hours the reaction mixture was quenched with water, solvent was removed under vacuum. The residue was diluted with water and extracted with ethylacetate. Combined organic layer was dried over Na 2 S0 4 and solvent was evaporated. Crude product was further purified on column chromatography.
- Step-3 To a stirred solution of trimethyl(2,2,2-trifluoro-l-(4-nitrophenyl)-l- phenylethoxy)silane (1.0 g, 2.71 mmol) in ethanol (10 mL) and water (5mL), was added ammonium chloride 0.3 g and Iron 1 g, and the reaction mixture was refluxed for 2hours. It was then filtered through celite and solvent was evaporated. Crude residue was further purified on column chromatography.
- Step-4 To a stirred solution of 4-(2,2,2-trifluoro- 1 -phenyl- 1- ((trimethylsilyl)oxy)ethyl)aniline (200 mg, 0.589 mmol) and 2-(4- (ethylsulfonyl)phenyl)acetic acid (134 mg, 0.589 mmol) in DCM (4 mL)' was added EDC (113 mg, 0.589 mmol) followed by HOBT (90 mg, 0.589 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum and crude product was purified on column chromatography.
- Step-5 To a stirred solution of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(2,2,2-trifluoro-l -phenyl- 1- ((trimethylsilyl)oxy)ethyl)phenyl)acetamide (1.0 g, 1.819 mmol) in THF (3 mL), was added TBAF (0.951 g, 3.64 mmol) at 0 °C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water, extracted further with DCM. The combined organic layer was dried over Na 2 S0 4 and solvent was removed.
- CHO-K1 cells stably transfected with RORyt are maintained in MEM-EBS with 5 % FBS, 1 % penicillin streptomycin solution and 1 mg/mL G418. The cells are seeded at a density of 200000 cells/mL in white 96 well flat bottom plate. Post 16-18 hours incubation, the cells are transiently transfected with pFR Luc (50 ng/well DNA) for four hours.
- the cells are then treated with different doses of the test compounds in MEM EBS media with 10 % FBS and 1 % penicillin streptomycin. DMSO is used as vehicle control. After 18-20 hours treatment, the cells are lysed with lysis buffer (40 mM HEPES, 20 mM EGTA, 50 mM ⁇ - glycerophosphate, 10 % glycerol and 1 % Triton X-100 in distilled water) for 0.5 hour and luminescence is read using Tecan Safire reader at 1000 milli second integration time.
- lysis buffer 40 mM HEPES, 20 mM EGTA, 50 mM ⁇ - glycerophosphate, 10 % glycerol and 1 % Triton X-100 in distilled water
- IC 50 (nM) values of the test compounds are presented in Table 1 wherein "+” refers to an IC 50 value in range of 0.01 nM to 50.00 nM, "++” refers to IC 50 value in range of 50.01 nM to 100.0 nM.
Abstract
Description
Claims
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PCT/IB2015/052198 WO2015145371A1 (en) | 2014-03-27 | 2015-03-25 | Ror-gamma modulators and uses thereof |
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JOP20200117A1 (en) | 2014-10-30 | 2017-06-16 | Janssen Pharmaceutica Nv | TRIFLUOROMETHYL ALCOHOLS AS MODULATORS OF ROR?t |
BR112017008852A2 (en) | 2014-10-30 | 2018-01-16 | Janssen Pharmaceutica N.V. | amide substituted thiazoles as roryt modulators |
JP6661630B2 (en) | 2014-10-30 | 2020-03-11 | ヤンセン ファーマシューティカ エヌ.ベー. | Thiazoles as modulators of RORγt |
FR3030518B1 (en) * | 2014-12-19 | 2018-03-23 | Galderma Research & Development | SULFONAMIDE DERIVATIVES AS REVERSE AGONISTS OF GAMMA RECTINTATIVE GAMMA ORPHELIN ASSOCIATED WITH RIN GAMMA RETINOIDS (T) |
MY189194A (en) | 2015-05-15 | 2022-01-31 | Aurigene Discovery Tech Ltd | Substituted tetrahydroquinolinone compounds as ror gamma modulators |
EP3101005A1 (en) | 2015-06-05 | 2016-12-07 | Lead Pharma Cel Models IP B.V. | Ror gamma (rory) modulators |
EP3101009A1 (en) * | 2015-06-05 | 2016-12-07 | Lead Pharma Cel Models IP B.V. | Ror gamma (rory) modulators |
WO2017010399A1 (en) * | 2015-07-10 | 2017-01-19 | 塩野義製薬株式会社 | COMPOUNDS HAVING RORγt INHIBITORY EFFECTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
BR112018011851A2 (en) | 2015-12-15 | 2018-12-04 | Astrazeneca Ab | isoindole compounds |
TWI757266B (en) * | 2016-01-29 | 2022-03-11 | 美商維它藥物有限責任公司 | Modulators of ror-gamma |
TW201803869A (en) | 2016-04-27 | 2018-02-01 | 健生藥品公司 | 6-aminopyridin-3-yl thiazoles as modulators of ROR[gamma]t |
MX2019000276A (en) * | 2016-07-14 | 2019-09-09 | Cadila Healthcare Ltd | Cyclopropyl derivatives as ror-gamma modulators. |
WO2018011747A1 (en) | 2016-07-14 | 2018-01-18 | Cadila Healthcare Limited | Polycyclic compounds as ror-gamma modulators |
US10196350B2 (en) * | 2016-12-05 | 2019-02-05 | Lead Pharma Holding B.V. | ROR gamma (RORγ) modulators |
WO2018193297A1 (en) | 2017-04-21 | 2018-10-25 | Cadila Healthcare Limited | Novel compounds as ror-gamma modulators |
JP2020524660A (en) | 2017-06-14 | 2020-08-20 | アストラゼネカ・アクチエボラーグAstrazeneca Aktiebolag | 2,3-Dihydroisoindole-1-carboxamides useful as ROR-gamma modulators |
EP3790865A1 (en) | 2018-06-18 | 2021-03-17 | Janssen Pharmaceutica NV | Phenyl substituted pyrazoles as modulators of roryt |
ES2928246T3 (en) | 2018-06-18 | 2022-11-16 | Janssen Pharmaceutica Nv | 6-aminopyridin-3-yl pyrazoles as RORyt modulators |
WO2019244002A1 (en) | 2018-06-18 | 2019-12-26 | Janssen Pharmaceutica Nv | Pyridinyl pyrazoles as modulators of roryt |
CA3103770A1 (en) | 2018-06-18 | 2019-12-26 | Janssen Pharmaceutica Nv | Phenyl and pyridinyl substituted imidazoles as modulators of roryt |
WO2020065682A1 (en) * | 2018-09-29 | 2020-04-02 | Translational Health Science And Technology Institute | Ror antagonists, their use and method of treatment comprising the said modulators |
CN113912597B (en) * | 2020-07-07 | 2023-06-13 | 赛诺哈勃药业(成都)有限公司 | ROR gamma inhibitor, preparation method and medical application thereof |
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WO2003068242A1 (en) * | 2002-02-11 | 2003-08-21 | Vertex Pharmaceuticals Incorporated | Phospholipids as caspase inhibitor prodrugs |
WO2004063147A1 (en) * | 2003-01-10 | 2004-07-29 | Novo Nordisk A/S | Salts and solvates of glucagon antagonists |
JP2007509846A (en) * | 2003-10-15 | 2007-04-19 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | Tetrahydro-naphthalene and urea derivatives |
US20050288340A1 (en) * | 2004-06-29 | 2005-12-29 | Pfizer Inc | Substituted heteroaryl- and phenylsulfamoyl compounds |
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WO2013171729A2 (en) * | 2013-01-08 | 2013-11-21 | Glenmark Pharmaceuticals S.A. | Aryl and heteroaryl amide compounds as rorgamat modulator |
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